Airway inflammation characterizes a number of severe lung diseases including asthma and chronic obstructive pulmonary disease (COPD). Events leading to airway obstruction include edema of airway walls, infiltration of inflammatory cells into the lung, production of various inflammatory mediators and increased mucous production. The airways of asthmatic patients are infiltrated by inflammatory leukocytes, of which the eosinophil is the most prominent component The magnitude of asthmatic reactions is correlated with the number of eosinophils present in lungs.
The accumulation of eosinophils is found dramatically in the lungs of asthmatic patients although there are very few in the lungs of a normal individual. They are capable of lysing and activating cells and destroying tissues. When activated, they synthesize and release inflammatory cytokines such as IL-1, IL-3, TNF-α and inflammatory mediators such as PAF, LTD4 and related oxygen species that can produce edema and broncho-constriction. Tumor necrosis factor (TNF-α) was also known to be involved in the pathogenesis of a number of autoimmune and inflammatory diseases. Consequently, manipulation of the cytokine signaling or biosynthetic pathways associated with these proteins may provide therapeutic benefit in those disease states. It has been well demonstrated that TNF-α production in pro-inflammatory cells becomes attenuated by an elevation of intracellular cyclic adenosine 3′,5′-monophosphate (cAMP). This second messenger is regulated by the phosphodiesterase (PDE) family of enzymes. The phosphodiesterase enzymes play an integral role in cell signaling mechanisms by hydrolyzing cAMP and cGP to their inactive 5′ forms. Inhibition of PDE enzymes thus results in an elevation of cAMP and/or cGP levels and alters intracellular responses to extra cellular signals by affecting the processes mediated by cyclic nucleotides. Since eosinophilis are believed to be a critical proinflammatory target for asthma, identification of the expression of the PDE 4 gene family in eosinophils led to PDE 4 as potential therapeutic target for asthma [Rogers, D. F., Giembycz, M. A., Trends Pharmacol, Sci., 19, 160-164 (1998); Barnes, P. J., Trends Pharmacol. Sci., 19, 415-423 (1998) herein incorporated by reference in their entirety].
The mammalian cyclic nucleotide phosphodiesterases (PDEs) are classified into ten families on the basis of their amino acid sequences and/or DNA sequence, substrate specificity and sensitivity to pharmacological agents [Soderling, S. H., Bayuga, S. J., and Beavo, J. A., Proc. Natl. Acad. Sci., USA, 96, 7071-7076 (1999); Fujishige, K, Kotera, J., Michibata, H., Yuasa, K., Takebayashi, Si, Okamura, K and Omori, K, J. Biol. Chem., 274, 18438-18445 (1999) herein incorporated by reference in their entirety]. Many cell types express more than one PDE and distribution of isoenzymes between the cells varies markedly. Therefore development of highly isoenzyme selective PDE inhibitors provides a unique opportunity for selective manipulation of various pathophysiological processes.
Phosphodiesterase type 4 (PDE4) is an enzyme which regulates activities in cells which lead to inflammation in the lungs. PDE4, a cAMP-specific and Ca+2-independent enzyme, is a key isozyme in the hydrolysis of cAMP in mast cells, basophils, eosinophils, monocytes and lymphocytes. The association between cAMP elevation in inflammatory cells with airway smooth muscle relaxation and inhibition of mediator release has led to widespread interest in the design of PDE4 inhibitors[Trophy, T. J., Am. J. Respir. Crit. Care Med., 157, 351-370 (1998) herein incorporated by reference in their entirety]. Excessive or unregulated TNF-α production has been implicated in mediating or exacerbating a number of undesirable physiological conditions such as diseases including osteoarthritis, and other arthritic conditions; septic shock, endotoxic shock, respiratory distress syndrome and bone resorption diseases since TNF-α also participates in the onset and progress of autoimmune diseases, PDE4 inhibitors may find utility as therapeutic agents for rheumatoid arthritis, multiple sclerosis and Crohn's disease. [Nature Medicine, 1, 211-214 (1995) and ibid., 244-248 herein incorporated by reference in their entirety].
Strong interest in drugs capable of selective inhibition of PDE 4 is due to several factors. Tissue distribution of PDE-4 suggests that pathologies related to the central nervous and immune systems could be treated with selective PDE-4 inhibitors. In addition, the increase in intracellular cAMP concentration, the obvious biochemical consequence of PDE-4 inhibition, has been well characterized in immuno-competent cells where it acts as a deactivating signal.
Recently the PDE family has grown to include four subtypes-PDE4A to PDE4D, each encoded by a distinct gene (British Journal of Pharmacology; 1999; v.128; p. 1393-1398), herein incorporated by reference in its entirety.
It has been demonstrated that increasing cAMP levels within these cells results in suppression of cell activation, which in turn inhibits the production and release of pro-inflammatory cytokines such as TNF-α. Since eosinophilis are believed to be a critical pro-inflammatory target for asthma, identification of the expression of the PDE-4 gene family in eosinophils led to the PDE-4 as a potential therapeutic target for asthma.
The usefulness of several PDE-4 inhibitors, unfortunately, is limited due to their undesirable side effect profile which include nausea and emesis (due to action on PDE-4 in the central nervous system) and gastric acid secretion due to action on PDE-4 in parietal cells in the gut Barnette, M. S., Grous, M., Cieslinsky, L. B., Burman, M., Christensen, S. B., Trophy, T. J., J. Pharmacol. Exp. Ther., 273,1396-1402 (1995) herein incorporated by reference in their entirety. One of the earliest PDE-4 inhibitors, Rolipram™, was withdrawn from clinical development because of its severe unacceptable side effect profile. Zeller E. et. al., Pharmacopsychiatr., 17, 188-190 (1984) herein incorporated by reference in its entirety. The cause of severe side effects of several PDE-4 inhibitor molecules in human clinical trials has recently become apparent.
There exist two binding sites on mammalian PDE-4at which inhibitor molecules may bind. Also PDE-4 exists in two distinct forms which represent different conformations. They are designated as High affinity Rolipram binding site PDE-4H and Low affinity Rolipram binding site PDE-4L [Jacobitz, S., McLaughlin, M. M., Livi, G. P., Burman, M., Trophy, T. J., Mol. Pharmaco., 50, 891-899 (1996) herein incorporated by reference in their entirety]. It was shown that certain side effects (vomiting and gastric acid secretion) are associated with inhibition of PDE-4H whereas some beneficial actions are associated with PDE-4L inhibition. It was also found that human recombinant PDE-4 exists id 4 isoforms A, B, C and D [Muller, T., Engels, P., Fozard, J. R., Trends Pharmacol. Sci., 17, 294-298 (1996) herein incorporated by reference in its entirety]. Accordingly, compounds displaying more PDE-4D isoenzyme selectivity over the A, B or C are found to have fewer side effects than Rolipram [Hughes. B et.al., Br. J. Pharmacol. 1996, 118, 1183-1191 herein incorporated by reference in their entirety]. Therefore, selective inhibitors of PDE-4 isozymes would have therapeutic effects in inflammatory diseases such as asthma and other respiratory diseases.
Although several research groups all over the world are working to find highly selective PDE-4 isozyme inhibitors, so far success has been limited. Various compounds have shown PDE-4 inhibition

SmithKline Beecham's “Ariflo” which has the formula A, Byk Gulden's Roflumilast which has the formula D and Bayer's Bay-19-8004 which has the formula E have reached advanced stage of human clinical trials. Other compounds which have shown potent PDE-4 inhibitory activity include Celltech's CDP-840 of the formula B, Schering Plough's D-4418 of the formula C, Pfizer's 5CP-220,629 which has the formula F, Parke Davis's PD-168787 which has the formula G and Wyeth's Filaminast which has the formula H. However, recently due to efficacy and side effects problems, Ariflo, CDP-840 and Bay-19-8004 were discontinued from clinical trials as a treatment for asthma. Other compounds of the formulae C and F are presently undergoing phase-1 clinical trials.
U.S. Pat. No. 4,933,351 describes Benzofuran 2-carboxy amides useful as inhibitors of leukoriene biosynthesis, a compound of the formula I and acceptable pharmaceutical carrier:
wherein:    Z is a bond, CR14═CR5;    X is O, S, SO or SO2;    R2 is H, OH, C1 to C20 alkoxy, including straight chain or branched chain, cycloalkyl, bicycloalkyl, tricycloalkyl or tetracycloalkyl;    Ar1-C1 to C3 alkoxy;    NR8Ar1, wherein R8 and Ar1 can optionally be joined to form a heterocyclic ring having 5 to 8 atoms;    —NR8Het;    —N(R8)CH2Ar1     —N(R13)—N(R13)2 wherein R13 is independently hydrogen, R8, R9,Ar1 or Het:    —NH—CH═C(Ar1)2;    —O(CH2)nNR8R9 wherein N is 2 to 4;    —Z—Ar1;
lower acyloxy-lower alkoxy
    —CH2OH;    —(CH2)nAr1 wherein in n is 0 to 3;    —(CH2)nCOOR6 wherein n is 0 to 6;    C1 to C20 alkyl; Ar1; Het; (CH2)nNR8R9     Wherein n is 1 to 3; or Het;
and R1, R3 R4, T and V are independently selected from                1. hydrogen;        2. alkyl having 1 to 6 carbon atoms;        3. alkenyl having 2 to 6 carbon atoms;        4. —(CH2)nM wherein n is 0 to 6 except when X is S and M is OR5, in which n is 1 to 6 and M is            a) —OR5;    b) halogen;    c) —CF3;    d) —SR5;    e) Ar1;    f) —COOR6;
Wherein R12 is H, C1 to C6 alkyl, or Ar1;    h) tetrazole;
    n)            —NHSO2R10 Wherein R10 is OH, C1 to C6 alkyl, CF3, C1 to C6 alkoxy, or Ar;        
    p) —SOR5     q) —CONR8R9;    r) —SO2NR8R9;    s) —SO2R5;    t) —NO2; or    u) —CN    or any two of R3,R4,T and V may be joined to form a saturated ring having 5 to 6 ring atoms, said ring atoms comprising 0,1 or 2 atoms selected from oxygen and sulfur, the remaining ring atoms been carbon;    each R5 is independently H, C1 to C6 alkyl, benzene, Ar1, perfluro-C1 to C4 allyl, CH2-R11 is C1 to C5 alkyldimethylamino,hydroxyl-C2 to C5 alkyl, CH2COOR6, or CH2CO—R7;    each R6 is independently H, or C1 to C6 alkyl;    each R7 is independently C1 to C6 alkyl, benzyl, Ar1, NR8R9, NHAr1 or O—C1 to C4 alkyl;    each R8 and R9 is independently H or C1 to C4 alkyl, or R8 and R9 may be joined through the N to which they are attached to form a heterocycloalkyl ring having 5 to 8 ring atoms;    each Het is independently an aromatic heterocyclic ring having 5 to 6 ring atoms, one or more of which is selected from N, O and S;    each Ar1 is independently 1- or 2-naphtyl, phenyl or mono- or disubstituted phenyl, wherein the substituents on phenyl are independently selected from C1 to C3 alkyl, I Br, Cl, F, COOR6, (CH2)n—NR8R9 wherein n is 0 to 2, methylenedioxy, C1 to C3 alkoxy, OH, CN,NO2, CF3, C1 to C4 acyl, NR8R9, S—C1 to C6 alkyl, SO—C1 to C6 alkyl, and SO2—C1 to C6 alkyl; and R14 and R15 are each independently H, C1 to C6 alkyl; or a pharmaceutically acceptable salts thereof
WO 94/08995 describes heterocyclic condensed benzoic acid derivatives as 5-HT4 receptor antagonists of formula (I-1) or a pharmaceutically accepted salts thereof:
Wherein X is O, or S;    R1 is hydrogen, amino, halo, C1-6alkyl, hydroxyl or C1-6alkoxy;    R2 is hydrogen, halo, C1-6alkyl, C1-6alkoxy, nitro, amino, or C1-6alkylthio;    R3 is hydrogen, halo, C1-6alkyl, C1-6alkoxy, or amino; and    R4 is hydrogen or C1-6alkyl.
WO 94/08995 also describes
Wherein    X is O or S    A represent a single bond, —CH2— or CO or A is (CH2)a—E—CH2)b where one of a and b is 0 and the other is 0 or 1 and E is O,S or NH;    R1 is hydrogen, amino, halo, C1-6alkyl, hydroxyl or C1-6alkoxy;    R2 is hydrogen, halo, C1-6alkyl, C1-6alkoxy, nitro, amino, or C1-6alkylthio;    R3 is hydrogen, halo, C1-6alkyl, C1-6alkoxy, or amino; and    R4 is hydrogen or C1-6alkyl.
WO 94/08995 also describes
Wherein    X is O or S    A represent a single bond, —CH2— or CO or A is (CH2)a—E—(CH2)b where one of a and b is 0 and the other is 0 or 1 and E is O,S or NH;    f and g are both hydrogen or together are a bond;    R1 is hydrogen, amino, halo, C1-6alkyl, hydroxyl or C1-4alkoxy;    R2 is hydrogen, halo, C1-6alkyl, C1-4alkoxy, nitro, amino, or C1-6alkylthio;    R3 is hydrogen, halo, C1-6alkyl, C1-6alkoxy, or amino; and    R4 is hydrogen or C1-6alkyl.
WO 94/08995 also describes
Wherein    X is O or S;    R1 is hydrogen, amino, halo, C1-6alkyl, hydroxyl or C1-6alkoxy;    R2 is hydrogen, halo, C1-6alkyl, C1-6alkoxy, nitro, amino, or C1-6alkylthio;    R3 is hydrogen, halo, C1-6alkyl, C1-6alkoxy, or amino; and    R41 and R411 are independently hydrogen or C1-6alkyl.
In formulae (I-1) to (I-4) inclusive:    Y is O or NH;    Z is of sub-formula (a), (b) or (c):
Wherein n1 is 0,1,2,3 or 4; n2 is 0,1,2,3 or 4; n3 is 2,3,4 or 5;    q is 0,1,2 or 3; p is 0,1 or 2; m is 0,1 or 2;    R5 is hydrogen, C1-12 alkyl, aralkyl or R5 is (CH2)z—R10 wherein z is 2 or 3 and R10 is selected from cyano, hydroxyl, C1-6alkoxy, phenoxy, C(O)C1-6alkyl, COC6H5, —CONR11R12, NR11COR12, SO2NR11R12 or NR11SO2R12, wherein R11 and R12 are hydrogen or C1-6alkyl; and    R6, R7 and R8 are independently hydrogen or C1-6alkyl; and    R9 is hydrogen or C1-10alkyl; or a compound of formula (I) wherein the CO—Y linkage is replaced by a heterocyclic bioisostere;
WO 01/58895-A1 describes novel compounds having the formula (i):
wherein R1 is C1-3alkyl optionally substituted with one or more fluorines;    R2 is CH2OCH3 or 2 or 3-tetrahydrofuranyl;    R3 is a pyrazole, imidazole or isoxazole group of a partial formula (A), (B) or (C)
    R4 is C1-3alkyl; and    R5 and R6, which may be same or different each represents C1-3alkyl, halogen, CF3 or CN;
U.S. Pat. No. 4,769,387 describes compounds of the formula:
wherein R is (1) hydrogen, (2) C1 to C4 alkyl, (3) C2 to C4 alkenyl, or (4) NR2R3, wherein R2 and R3 are independently selected from hydrogen, C1 to C4 alkyl or hydroxyl, but R2 and R3 are not simultaneously hydroxyl;    X (1) oxygen, (2) sulfur, (3) SO2, or (4) NR4 wherein R4 is (1) hydrogen, (2) C1 to C6 alkyl, (3) C1 to C6 alkoyl, or (4) aroyl;    A is selected from C1 to C6 alkylene and C2 to C6 alkenylene;    Y is selected independently at each occurrence from (1) hydrogen, (2) halogen, (3) hydroxy, (4) cyano (5) halosubstituted alkyl, (6) C1 to C12 alkyl, (7) C2 to C12 alkenyl, (8) C1 to C12 alkoxy, (9) C3 to C8 cycloalkyl, (10) aryl, (11) aryloxy, (12) aroyl, (13) C1 to C12 arylalkyl, (14) C2 to C12 arylalkenyl, (15) C1 to C12 arylalkoxy, (16) C1 to C12 arylthioalkoxy, and substituted derivatives of (17) aryl, (18) aryl-oxy, (19) aroyl, (20) C1 to C12 arylalkyl, (21) C2 to C12 arylalkenyl, (22) C1 to C12 arylalkoxy, or (23) C1 to C12 arylthioalkoxy, wherein substituents are selected from halo, nitro, cyano C1 to C12 alkyl, alkoxy, and halosubstituted alkyl; the number n is 0-4; the group(s) Y may be substituted from any of the positions on the aryl rings;    and M is hydrogen, a pharmaceutically acceptable cation, aroyl, or C1 to C12 alkoyl.
U.S. Pat. No. 3,897,453 describes dibenzofuran and dibenzothiophene derivatives of general formula IZ—CHR1R2  (I)
In which Z is
wherein R1 is COOH, CHO, or CH2OH including functional derivatives thereof; R2 is H or alkyl of 1-4 carbon atoms; R3 is H, alkyl, alkoxy, alkanoyl, monoalkylamino, dialkylamino, or acylamino, each of up to 4 carbon atoms, F, Cl, Br, I, OH, NH2, NO2, CN, or CF3; and Y is O or S; with the proviso that at least one of R2 and R3 is other than H; and the physiologically acceptable salts thereof.
WO 98/09934 describes compounds of formula I
Wherein M is a natural (L) alpha amino acid derivative having the structure
    X is O, S, S(O)n, CH2, CO, or NRQ;    RQ is hydrogen, C1-C6 alkyl or —C1-C6 alkyl-phenyl; R is aside chain of a natural alpha amino acid;    R1 is C1-C5 alkoxy, hydroxy, or —NHOR5;    R2 and R4 are independently hydrogen, —C1-C5 alkyl, phenyl-NO2, halogen, —OR5, —CN, —CO2R5, —SO3R5, —CHO, —COR5, —CONR5R6, —(CH2)nNR5R6, —CF3, or —NHCOR5;    Each R5 and R6 are independently hydrogen, C1-C5 alkyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, amides and prodrugs thereof.